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Toxicology Mechanism
Mechanisms of Toxicology
| Question | Answer |
|---|---|
| Receptor Ligand | Stereospecific. TCDD (Dioxin), PCBs, Estrogen |
| Dioxin (TCDD) Characteristics | Heating organic compounds in the presence of chlorine (chemical synthesis procedures). Planar, stable (in body and environment), lipid soluble (slow elimination, not kidneys). Example : agent orange. |
| Dioxin Toxicity | Animals : teratogen, male reproductive system, cancer (liver), wasting, change gene expression of P450s, Humans : chlorane (skin lesions, Russian politician), Sensitivities (Guinea Pig >>> Hamster, humans unknown). |
| Dioxin Mechanism | Mechanism: Bind Ah receptor in cytosol (AhR-D) -> Nucleus (ARNT) -> change gene expression (DRES) -> proteins like p450's and others -> cause (unsure which) toxicity |
| PCBs | Less toxic than dioxin. Chlorine can vary attachment site. Some are dioxin like with less affinity. Meta and para : higher affinity, change gene transcription. Ortho : non-planar, no affinity, different kind of toxicity. |
| Estrogen | Estrogen like effects : Chrlorine compounds (like PCB's), furane coumadin (soy), diethylstilbetrol, Tamoxifen, RU489 (Antagonist) |
| Interference with Excitable Membranes | Tetrodotoxin (Na channels), Organic Solvents (membrane fluidity), DDT (Na channel closing), Organophosphates (acetylcholinesterase). (All inhibit) |
| Volatile Organic Solvents | Hydrocarbons and alcohols. CNS : disorientation, euphoria, unconscious, paralysis, convulsions, death because of respiratory and heart paralysis. Mechanism unknown. Cross lipid membranes. HASH DUDs get euphoria. |
| Specific Volatile Organic Solvents and Specific Effects | Lower doses than CNS. Benzene : hematopoesis (metabolized), CCl4 : hepatotoxic (metabolized), methanol : renal + metabolic acids (formic acid), N-hexane : peripheral neuropathy, ethylene glycol ethers : reproductive system, dixoane (not dioxin) : cancer |
| Ethanol | CNS : a : depres, c: WK, Liver: steat, hepa, coll scar, cirr, portal HT, GI : gastritis, peptic ulcers, Panc, Heart : vasodili, acute hypotherm, myop, arrhyth, Endocr, Cancer : GI, liver, FAS, Immune WIPED (WK, Immune, portal HT, Endocrine, Dilitation) |
| Inhibit Energy Production (ATP) | Change membrane integrity, Ion Pump, protein synthesis, heart and brain most effected. Examples : CO2 : compete for Hb, NO2- : Hb oxidation, CN, H2S, Azide : Mito electron transport, Nitrophenol : uncouple oxidative phosphorylation, Fluroacetate : Krebs |
| NO2- | Sources : Drugs, Food preperation : looks like table salt, well water : bacteria in spawn stomachs have increased pH get NO3- to NO2-. |
| NO2- Side Effects | Cyanosis : chocolate brown blood, decreased BP, CV collapse, Abdominal pain, GI irritation : nausea, vomiting, headache, vertigo, change respiration and pulse, inc IOP, inc ICP (intracranial P), coma (70% metHb), cancer from meat CAR CIVIC(nitrosamine) |
| NO2- Mechanism and Treatment | +2 Hb -> +3 Methb -> binds NO2-. 40% toxic, 70-80% death : hypoxia and vasodilitation (NO). Treatment : maintain ciruclation and respiration, transfusions, methylene blud (antidote), Ascorbic acids : works in long term only, not acute. |
| Methylene Blue Mechanisms | +3 MetHb + NADH -> +2. Excess +3 MetHb needs methylene blue as catalyst via MB reductase (Diaphorase II) from NADPH |
| CN- | Industry, fumigant, criminal, fires, nitroprusside metabolism. Rare but BAD. Heart and brain. Headache, anxiety (early), nausea, vomiting, arrhythmias, other CV, pulmonary edema, coma, seizures, shock, no cyanosis till resp failure, death. ACCESS |
| CN- Treatment | Support heart, anticonvulsants, NaHCO3 for acidosis, 100% oxygen. antidotes : NO2- (+2 to +3) to push CN off, Thiosulfate donates sulfur to increase metabolism of CN- with Rhodanese. |
| Binding of Biomolecules | Binding proteins : change enzyme or membrane transport. Examples : CN-, CO2 : Hb, Heavy Metals : -SH group. Decrease intracellular thiols : GSH : protective, examples : acetaminophen depletes GSH |
| Acetaminophen | "Therapeutic misadventure". Liver (#1 drug induced liver damage). Metabolism: Good route: PAPS Sulfonotransformation + UDP-GA Gluconation -> 95% conjugated. Bad route: p450 -> NAPQ1 -> Bind macromolecules (hepatocytes) |
| Acetaminophen vs Aflatoxin | Acetaminophen : Hepatotoxicity via parenchymal damage (acute), central lobar lesions (around central vein). Aflatoxin : Hepatotoxicity via parenchymal and bile duct epithelial cells, peripheral lesions |
| Aflatoxin Characteristics | Mycotoxin from mold on grains and nuts (aspergillow), low dose, long exposure, acute liver damage and cancer. p450s metabolize -> epoxide (active) -> bind DNA and proteins (macromolecules). |
| Aflatoxin Mechanism | Mechanism: Good route : AFB1 -> p450s -> oxidation to non-toxic. Bad route : p450 -> epoxide (active) -> bind proteins : acute liver toxicity OR bind DNA : liver cancer. GSH also plays a role. Bioactivity causes binding which causes issues. |
| Aflatoxin Susceptibility | Age. G: gender. B: metabolism (variations p450), immunologic reactions, reserve capacity, absorption, distribution, comorbid. E: inflammation (co-inflammatory drug, shift to left), exposure, nutrition, GSH : diurnal, decreased in fasting. |
| Nucelic Acids | DNA = nucleophile. Electrophiles bind (free radicles) -> cell death OR somatic mutation -> cancer |
| Benzopyrine | Polycyclic aromatic hydrocarbon. p450 activates. Burning carbon containing fuels (charcoal, tar), bay binds DNA. |
| Benzopyrine Metabolism | p450 -> epoxide (active) -> epoxide hydrase -> dihydrobiol (no DNA binding, still lipophyilic) -> p450s -> epoxide (epoxide hydrase can't catalyze) -> bind DNA -> cancer OR epoxide hydrase conjugationto inactive (minor route). |
| Benzopyrine Mechanism | BP + G-C -> BP-G thinks A -> A-T, mutation : permanent and heritable, start carcinogenesis -> NEED INITIATOR THEN PROMOTER |
| Food Additives | Delany says no to anyhthing that causes cancer but everyone eats so even 1/10,000 SEs is bad, because a million billion people times 1/10,000 = ALOT with cancer. |
| Drug Administration | DES (anti miscarriage 50s) -> teen daughters in 70s with vaginal cancer (long latent period). Smoking increases lung cancer. To test, look at animals : bioassay, long latency, massive doses (spontaneous tumors do happen) extrapolate back a "safe dose". |
| Xenobiotic | Metabolized and eliminated OR becomes reactive intermediate which can covalently bind and cause 1. peroxidation of lipid membrane (injury and necrosis), 2. Immune response (Hapten -> Ag), or 3. Bind macromolecules DNA and proteins (cancer). |
| Examble of Xenobiotic | CCl4 -> CCL3-, O2-, OH-, etc... Membrane FAs with unsaturated side chains. LF -> opens to H-C* + H*. CCl4 -> p450 -> CCl3 (~stable) + LH -> CHCl3 + H* + L* -> L* + O2 -> LOO* (peroxil)+ LH -> LOOH (Peroxide lipid toxic with break down) + L* (cycle). |
| ROS | 1 e- reduction of O2 -> O2-* (Superoxide) -> H2O2 both + Fe+2 -> OH* (hydroxyl) -> H20 (each time lose 1 e-) * = ROS, reactive and toxic. Paraqual forms ROS in cycle with NADPH + p450 -> NADP+ and O2 -> O2- : redox cycling. |
| Results of ROS | Lipid peroxidation, GSH ox -> Disulfide, protein oxidation -> disulfide, depletion of NADH (reducin equivalents) -> lung problems. |
| Protection against ROS | O2 -> O2-* + SOD -> H2O2 Both + Fe+2 -> OH* -> H20. H202 + GSH -> GSPx -> H20 + GSSH. GSSH + NADPH -> GSRed -> NADP+. SOD dec O2-*, GSPx dec H202 (less reactive than O2-*, GSRed inc GSH, Vit C + * -> H20, Vit E -> lipid + Vit C -> H20 soluble. |
| No protection | 1. Vit E or Vit C deficiency, 2. Selenium deficiency (GSPx), 3. GSH depletion (malnutrition, fasting), 4. Genetic (SOD deficient). ALSO in ETC e- coupled tightly, from O2 right to H2O. |
| Oxidant | NO2 <-> N2O2 (gas). Silos : bacteria incomplete breakdown of NO3-. Smog : nitrogen oxides + O2 + sun -> NO2 + O3 (ozone, toxic). SEs: bronchiolitis obliterans (silo fillers disease, can be 100,000 ppm) : small airway of lungs (100 ppm bad, 200 kills). |
| Oxidant Mechanism | Direct + H20 (mucous) -> HNO3. Oxidation -> lipid peroxidiation -> apoptosis. In lungs get clara cells for normal cilia. |
| Calcium Issues of Homeostasis | Increase cytosolic Calcium -> issues with cytoskeleton -> increase proteases, phospholipases and endonucleases (chompy, chompy), also issues with mito. |
| Increased Gene Expression | Like Dioxin |
| Selective Cell Death | MPTP -> parkinson’s, Thalidomide -> teratogen -> arm buds. |
| Teratogens | Doses non-toxic to mom. Thalidomide -> arm buds. Window : organogenesis (critical periods). FAS, Vit A (high doses), synthetic retinoids (Accutane), Cocaine, Methyl Hg. Seg I = A + B + C, Seg II = B, Seg III = B + C (A = sperm, B = org, C = to wean). |
Created by:
chavezc3
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